The generation of induced pluripotent stem (iPS) cells is an innovative approach for generating autologous pluripotent stem cell lines for individualized cell therapy. Our research will use human skeletal muscle derived myoblasts rather than terminally differentiated fibroblasts for non-viral generation of iPS and their differentiation int cardiac progenitor cells. The hypothesis is that skeletal myoblasts (SMs) are superior candidates for induction to pluripotent state with fewer factors either alone or in combination with treatment with small molecules. Thus iPS derived cardiac progenitors may be readily generated with the use of cardiogenic small molecules, purified to generate off shelf universal cardiac cells. The direct generation of progenitors from iPS cells with specific small molecule may be a major current paradigm shift in stem cell therapy. We further propose that use of iPS derived cardiovascular progenitors will allow successful regeneration of infarcted myocardium without the risk of tumorgenecity. The hypotheses will be tested in the following specific Aims. Specific Aim-1will generate iPS cells from human SMs using small molecules; Specific Aim-2 will focus on developing strategies to direct iPS cells to cardiac and vascular progenitors; Specific Aim-3 will exploit the power of Ischemic preconditioning signaling in regulating survival and engraftment of iPS -progenitors in the ischemic tissue for effective regeneration; Specific Aim 4 will test that transplantation of iPS - progenitors and preconditioned progenitors effectivel regenerates infarcted myocardium and reverses fibrosis in murine and pre-clinical porcine heart models. The end points of the in vivo studies will be reversal of fibrosis through myoangiogenic differentiation of the engrafted progenitor cells, functional integration of developing cardiac myocytes into the host heart, attenuation of infarct size and the functional benefits in terms of improved global heart function. These studies will involve multidisciplinary approach which will employ state of the art molecular biology, histochemical and immunohistochemical techniques and well integrative physiology involving well established experimental animal model, and transthoracic ultrasonography for animal heart function. These studies are expected to facilitate robust cardiac differentiation and cardiomyocyte purification resulting in generation of unlimited number of cardiac progenitor cells from SM-iPS for restoring damaged myocardium without the risk of tumor formation.